Overexpression of ErbB2 receptor inhibits IGF-I-induced Shc-MAPK signaling pathway in breast cancer cells.

Abstract

Overexpression of the ErbB2 receptor in one-third of human breast cancers contributes to the transformation of epithelial cells and predicts poor prognosis for breast cancer patients. We report that the overexpression of ErbB2 inhibits IGF-I-induced MAPK signaling. IGF-I-induced MAPK phosphorylation and MAPK kinase activity are reduced in ErbB2 overexpressing MCF-7/HER2-18 cells relative to control MCF-7/neo cells. In SKBR3/IGF-IR cells, reduction of ErbB2 by antisense methodology restores the IGF-I-induced MAPK activation. The inhibition of IGF-I-induced MAP kinase activation in ErbB2 overexpressing breast cancer cells is correlated with decreased IGF-I-induced Shc tyrosine-phosphorylation, leading to a decreased association of Grb2 with Shc and decreased Raf phosphorylation. However, IGF-I-induced tyrosine-phosphorylation of IGF-I receptor and IRS-I and AKT phosphorylation were unaffected by ErbB2 overexpression. Consistent with these results, we observed that the proportion of IGF-I-stimulated proliferation blocked by the MAPK inhibitor PD98059 fell from 82.6% in MCF-7/neo cells to 41.2% in MCF-7/HER2-18 cells. These data provide evidence for interplay between the IGF-IR and ErbB2 signaling pathways. They are consistent with the view that the IGF-IR mediated attenuation of trastuzumab-induced growth inhibition we recently described is dependent on IGF-I-induced PI3K signaling rather than IGF-I-induced MAPK signaling.

• Authors: Yuhong Lu, Xiaolin Zi, Yunhua Zhao, Michael Pollak
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 313 Issue 3 Pg. 709-15 (Jan 16 2004) ISSN: 0006-291X [Print] United States
• PMID: 14697248 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Adaptor Proteins, Vesicular Transport
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Culture Media, Serum-Free
• Enzyme Inhibitors
• Flavonoids
• GRB2 Adaptor Protein
• GRB2 protein, human
• Ligands
• Oligonucleotides
• Oligonucleotides, Antisense
• Proteins
• Proto-Oncogene Proteins c-fos
• Proto-Oncogene Proteins c-jun
• SHC1 protein, human
• Shc Signaling Adaptor Proteins
• Src Homology 2 Domain-Containing, Transforming Protein 1
• Tyrosine
• Insulin-Like Growth Factor I
• Receptor, ErbB-2
• Receptor, IGF Type 1
• Trastuzumab
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Adaptor Proteins, Signal Transducing
• Adaptor Proteins, Vesicular Transport (metabolism)
• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Blotting, Western
• Breast Neoplasms (metabolism)
• Cell Division
• Cell Line, Tumor
• Culture Media, Serum-Free (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Flavonoids (pharmacology)
• GRB2 Adaptor Protein
• Humans
• Insulin-Like Growth Factor I (metabolism)
• Ligands
• MAP Kinase Signaling System
• Oligonucleotides (pharmacology)
• Oligonucleotides, Antisense (pharmacology)
• Phosphorylation
• Precipitin Tests
• Prognosis
• Protein Binding
• Proteins (metabolism)
• Proto-Oncogene Proteins c-fos (metabolism)
• Proto-Oncogene Proteins c-jun (metabolism)
• Receptor, ErbB-2 (metabolism)
• Receptor, IGF Type 1 (metabolism)
• Shc Signaling Adaptor Proteins
• Signal Transduction
• Src Homology 2 Domain-Containing, Transforming Protein 1
• Trastuzumab
• Tyrosine (metabolism)